Process for producing 5-substituted oxazole compounds and 5-substituted imidazole compounds

ABSTRACT

A process for producing heterocyclic compounds which are useful as pesticides, drugs, fungicidal materials or intermediates thereof. TosMIC is reacted with an aldehyde or an imino compound: 1) in a solvent mixture of an aprotic solvent with a protic solvent in the presence of a base, 2) in the presence of a phase-transfer catalyst and an inorganic base, or 3) in the presence of an inorganic base. Thus, a desired product can be efficiently obtained using a solution without isolating TosMIC which is irritating and unstable, has a low decomposition point and shows explosivity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national phase application under 35 U.S.C. §371 of International Patent Application No. PCT/JP02/02704, filed onMar. 20, 2002, and claims the benefit of Japanese Patent ApplicationNos. 2001 - 84092, 2001 - 84183, and 2001 - 84184, all of which werefiled on Mar. 23, 2001. The International Application was published inJapanese on Oct. 3, 2002, as International Publication No. WO 02/076958A1 under PCT Article 21 ( 2 ), the contents of which are incorporatedherein by reference in its entirety.

1. Field of the Invention

The present invention relates to processes for the preparation ofheterocyclic compounds useful as excellent agricultural chemicals,drugs, functional materials or intermediates for producing them.

2. Background Art

A method of using an aldehyde and p-tolylsulfonylmethylisocyanide(hereinafter abbreviated as TosMIC) is generally known as a particularlyuseful process among those for synthesizing 5-substituted oxazolecompounds. Generally, the process involves reacting an aldehyde withTosMIC in methanol in the presence of potassium carbonate. In addition,another known method involves the reaction in dimethoxyethane andmethanol in the presence of an ion exchange resin (Ambersep 9000H-)(Tetrahedron Letters, 1972, 2369; Lect Heterocycl. Chem., 1980, (5), SI11-122; Tetrahedron Letters, 1999, 5637-5638, and others).

Methods for synthesizing 5-substituted imidazoles with TosMIC are alsoknown. Generally, an imino compound is reacted with TosMIC in analcohol-type solvent in the presence of potassium carbonate (TetrahedronLetters, 1976, 143-146; J. Org. Chem., Vol. 42 (7), 1997 1977,1153-1159; Tetrahedron Letters, 2000, 5453-5456; and Tetrahedron, 53(6), 2125-2136, 1997).

In all of the said processes, TosMIC is handled as crystals. Because ofthis, complicated isolation procedures including concentration,crystallization, separation of solvents, and drying are required,depending on the conditions, when the compound is produced industrially.Besides, a decrease in TosMIC production yield is unavoidable due toloss of product in filtrates. Furthermore, TosMIC is irritating,unstable and explosive with a low decomposition point. Its isolationshould be avoided for safety reasons.

As described above, it is preferable not to isolate TosMIC when safetyis taken into account. To handle TosMIC without isolating it, it isinevitable to use the reaction solution itself or a solution of anotherextract solvent after TosMIC is synthesized and post-treatments aredone. It has been essential to develop safer processes for producing5-substituted oxazoles and 5-substituted imidazoles with TosMIC in asolution without isolating it.

BRIEF SUMMARY OF THE INVENTION

It is an object of the present invention to provide safer and moreefficient processes for the preparation of 5-substituted oxazoles and5-substituted imidazoles.

The inventors studied in earnest to achieve this object, and found thata target compound could be obtained in good yield, even if TosMIC wasused without isolation. TosMIC was reacted with an aldehyde or iminocompound (1) in a mixed solvent of an aprotic solvent with a proticsolvent in the presence of a base, (2) in the presence of aphase-transfer catalyst and an inorganic base, or (3) in the presence ofan organic base.

In one aspect, the present invention relates to a process for thepreparation of a 5-substituted oxazole or 5-substituted imidazole,characterized in that TosMIC is synthesized fromN-(p-tolylsulfonylmethyl)formamide with phosphorus oxychloride, phosgeneor diphosgene, and a tertiary amine, to form a TosMIC solution which isnot isolated and purified as crystals, and reacting the TosMIC solutionwith an aldehyde or a compound represented by Formula [I]: R¹CH═NR²(wherein, R¹ and R² are optionally substituted phenyl, optionallysubstituted heterocyclic group or optionally substituted alkyl).

In some embodiments, the TosMIC solution is reacted with an aldehyde ora compound of Formula [I] in a mixed solvent of an aprotic solvent and aprotic solvent in the presence of a base.

In some embodiments, the protic solvent is one or more solvents selectedfrom the group consisting of water, C₁ to C₁₀ alcohols and mono- orpoly-alkylene glycols.

In other embodiments, the aldehyde or the compound of Formula [I] isreacted with TosMIC in the presence of a phase-transfer catalyst and aninorganic base.

In some embodiments, the aldehyde or the compound of Formula [I] isreacted with TosMIC in the presence of an organic base.

In some embodiments, the organic base has a pKa of 12 or more.

In some embodiments, the the organic base is1,8-diazabicyclo[5.4.0]undec-7-ene or 4-(N,N-dimethylamino)pyridine.

In other embodiments, the aldehyde is an unsubstituted or substitutedaromatic aldehyde.

DETAILED DESCRIPTION OF THE INVENTION

Forms to implement the present invention are described in detail.

Aldehydes having any structure can be used for producing 5-substitutedoxazoles in the present invention. Actual examples of preferredaldehydes include aldehydes having aromatic hydrocarbon groups such asphenyl, naphthyl or anthracenyl; and aldehydes having aromaticheterocyclic groups such as furyl, thienyl, oxazolyl, thiazolyl, pyridylor N-methylpyrroloyl. These groups may be optionally substituted withvarious functional groups. Actual examples of such functional groupsinclude halogen, optionally substituted alkyl, optionally substitutedalkoxy, nitro, cyano, hydroxyl, optionally substituted amino andoptionally substituted alkoxycarbonyl. Examples of alkyl groups includestraight-chain or branched alkyl groups having 1 to 12 carbons, such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl andt-butyl. Examples of alkoxy groups include straight-chain or branched,lower alkoxy groups having 1 to 4 carbons such as methoxy, ethoxy andpropoxy. Further, examples of substituents of the functional groupsinclude halogens, nitro, alkoxy and cyano.

In Formula [I] representing imino compounds, which are startingmaterials for producing 5-substituted imidazoles, R¹ and R² are the sameor different. Actual examples of R¹ and R² include straight-chain orbranched alkyl groups having 1 to 12 carbons, such as methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, i-butyl or t-butyl; aromatichydrocarbons such as phenyl, naphthyl or anthracenyl; and aromaticheterocyclic groups such as furyl, thienyl, oxazolyl, thiazolyl, pyridylor N-methylpyrroloyl. These groups may be optionally substituted withvarious functional groups. Actual examples of such functional groupsinclude, for alkyl groups, halogen, optionally substituted alkoxy,nitro, cyano, hydroxyl, optionally substituted amino and optionallysubstituted alkoxycarbonyl. Examples of alkoxy groups includestraight-chain or branched, lower alkoxy groups having 1 to 4 carbonssuch as methoxy, ethoxy and propoxy. Further, examples of substituentsof the functional groups include halogens, nitro, alkoxy and cyano.Examples of substituents of aromatic hydrocarbon and aromaticheterocyclic groups include halogens, optionally substituted alkyl,optionally substituted alkoxy, nitro, cyano, hydroxyl, optionallysubstituted amino and optionally substituted alkoxycarbonyl. Examples ofalkyl groups include straight-chain or branched alkyl groups having 1 to12 carbons, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,i-butyl and t-butyl. Examples of alkoxy groups include straight-chain orbranched, lower alkoxy groups having 1 to 4 carbons such as methoxy,ethoxy and propoxy. Further, examples of substituents of the substituentgroups include halogens, nitro, alkoxy and cyano.

An imino compound can be produced from a reaction of the correspondingaldehyde with an amine and be used without isolating and purifying it inthe process of the present invention.

TosMIC produced by either of the generally applied methods describedbelow can be used: N-(p-tolylsulfonylmethyl)formamide (TosMFA) isreacted with phosphorus oxychloride in dimethoxyethane (DME) (OrganicSynthesis, Vol. 57, 102-106; Synthesis, 400-402 (1985); and TetrahedronLetters, 1972, 2367), or a method using phosgene or diphosgene (Angew.Chem. Int. Ed. Engl. 16 (1997), 259; Angew. Chem., 77 (1965), 492; andDE 4032925).

Each of the processes is described in the following.

Process 1: Reaction of a TosMIC solution with an Aldehyde or a Compoundof Formula [I] in a Mixed Solvent of an Aprotic Solvent and a ProticSolvent in the Presence of a Base.

Any organic and inorganic bases can be used as the base. Actual examplesof organic bases include alkylamines such as dicyclohexylamine,diisopropylamine, diethylamine, triethylamine, tributylamine anddiisopropylethylamine; alkylanilines such as N,N-dimethylaniline;heterocyclic amines such as piperidine, pyrrolizine,2,2,6,6-tetramethylpiperidine, morpholine, piperazine, imidazole,1-ethylpiperidine, 4-methylmorpholine, 1-methylpyrrolizine,1,4-diazabicylo[2.2.2]octane and 1,8-diazabicyclo[5.4.0]-7-undecene;quarternary ammonium salts such as benzyltriethyl ammonium chloride andmethyltrioctyl ammonium chloride; or diamines such asN,N,N′,N′-tetramethylethylenediamine. Actual examples of inorganic basesinclude sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium hydrogen carbonate and potassium hydrogencarbonate.

It is preferable to use one or more solvents selected from the groupconsisting of water, C₁ to C₁₀ alcohols and mono- or poly-alkyleneglycols as the protic solvent. Actual examples of protic solventsinclude water; alcohols such as methanol, ethanol and propanol; andglycols such as ethylene glycol, diethylene glycol and ethylene glycolmonomethyl ether. Among them, methanol, ethylene glycol and2-methoxyethanol are preferably used.

Preferred aprotic solvents are those that can be used for synthesizingor extracting TosMIC. Examples of aprotic solvents include halogen-typesolvents such as methylene chloride, chloroform, dichloroethane andmethylene chloride; aromatic hydrocarbon-type solvents such as benzene,chlorobenzene, toluene, xylene, nitrobenzene and benzonitrile;ester-type solvents such as methyl acetate, ethyl acetate and isopropylacetate; ketone-type solvents such as acetone, methyl ethyl ketone,diethyl ketone and methyl isobutyl ketone; ether-type solvents such asdiethyl ether and tetrahydrofuran; and polar solvents such asacetonitrile. Such solvents can be used alone or in any combination oftwo or more.

The reaction is carried out using 2.0 moles or more, preferably 2.0 to2.5 moles, more preferably 2.0 to 2.2 moles, of a base per one mole ofthe aldehyde or compound of Formula [I]. Any amount of TosMIC can beused. It is preferably in the range of 0.8 to 1.5 moles, more preferably0.9 to 1.2 moles per one mole of the aldehyde. Any amount of a proticsolvent can be used if it can dissolve a base to some extent. It isfavorable to use 1 liter or more per one mole of the aldehyde orcompound of Formula [I] used. Any amount of an aprotic solvent can alsobe used if it dissolves TosMIC. An aprotic solvent can be mixed with aprotic solvent at any mixing ratio. The ratio can be set at discretion.

In an exemplary reaction, an aldehyde or a compound of Formula [I] ismixed with a TosMIC solution and a base dissolved or suspended in aprotic solvent, and reacted at a temperature from 0° C. to the boilingpint of the solvent used, preferably from 20 to 60° C. In this case,they can be reacted in the co-presence of a phase-transfer catalyst. Thereaction is favorably carried out in a nitrogen stream or nitrogenatmosphere. The reaction time will differ depending on compounds to bereacted and reaction conditions. It is usually from about severalminutes to 48 hours. After the reaction is completed, the reactionsolution is cooled down, if necessary, and standard post-treatmentsyield the target compound.

Process 2: Reaction of an Aldehyde or a Compound of Formula [I] withTosMIC in the Presence of a Phase-Transfer Catalyst and an InorganicBase.

Examples of phase-transfer catalysts suitable for use in the reactionsof the present invention include onium salts such as quaternary ammoniumsalts and quaternary phosphonium salts, crown compounds and organicbases. Actual examples of quaternary ammonium salts include tetramethylammonium hydroxide, tetraethyl ammonium hydroxide, tetrabutyl ammoniumhydroxide, trimethylbenzyl ammonium hydroxide, tetramethyl ammoniumbromide, tetraethyl ammonium bromide, tetrabutyl ammonium bromide,triethylbenzyl ammonium bromide, trimethylphenyl ammonium bromide,tetramethyl ammonium chloride, tetraethyl ammonium chloride, tetrabutylammonium chloride, triethylbenzyl ammonium chloride, trimethylphenylammonium chloride, trioctylmethyl ammonium chloride, tributylbenzylammonium chloride, trimethylbenzyl ammonium chloride, N-laurylpyridinium chloride, N-benzyl picolinium chloride, tricaprylmethylammonium chloride, tetramethyl ammonium iodide, tetrabutyl ammoniumiodide and tetrabutyl ammonium sulfate. Examples of quaternaryphosphonium salts include tetraethyl phosphonium chloride, tetraethylphosphonium bromide, tetraethyl phosphonium iodide, tetrabutylphosphonium bromide, tetraphenyl phosphonium bromide and triphenylbenzylphosphonium bromide. Examples of crown compounds include crown etherssuch as 15-crown-5,18-crown-6, and cryptands. Examples of organic basesinclude 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-ene,6-dibutylamino-1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamineand N,N-dimethylaminopyridine. Any amount of a phase-transfer catalystcan be used. It is in a range of 0.0001 to 5 moles, preferably 0.01 to0.5 equivalent moles per one mole of the aldehyde or compound of Formula[I] used.

Examples of inorganic bases suitable for use in the present inventioninclude sodium hydroxide, potassium hydroxide, lithium hydroxide,potassium carbonate, sodium carbonate, potassium hydrogen carbonate andsodium hydrogen carbonate. Any amount of an inorganic base can be used.It is preferably between 0.5 and 10 moles, and more preferably 1.0 and 3moles per one mole of the aldehyde used.

Actual examples of solvents suitable to use for the reaction includewater; halogen-type solvents such as methylene chloride, chloroform anddichloroethane; aromatic hydrocarbon-type solvents such as benzene,toluene, xylene, benzonitrile, benzotrifluoride and chlorobenzene;ester-type solvents such as methyl acetate, ethyl acetate and isopropylacetate; ketone-type solvents such as acetone, methyl ethyl ketone,diethyl ketone and methyl isobutyl ketone; ether-type solvents such asdiethyl ether and tetrahydrofuran; and polar solvents such asacetonitrile. Particularly preferred are solvents that can be used forsynthesizing TosMIC or extracting it after post-treatments. Examplesinclude halogen-type solvents such as methylene chloride; aromatichydrocarbon-type solvents such as toluene, xylene and chlorobenzene;ester-type solvents such as ethyl acetate; ketone-type solvents such asmethyl isobutyl ketone; THF and acetonitrile. Such solvents can be usedalone or in any combination of two or more. A mixed solvent of waterwith the exemplified solvents other than water is particularlypreferred. Any amount of solvent can be used. Generally, the solvent ispresent in a range of 1 to 1,000 times by weight, preferably 5 to 100times by weight, based on the weight of the aldehyde or compound ofFormula [I] used.

In an exemplary reaction, an aldehyde or a compound of Formula [I] ismixed with TosMIC or its solution in an appropriate solution, and aninorganic base dissolved in water and a phase-transfer catalyst areadded to react at a temperature ranging from 0° C. to the boiling pointof the solvent used, preferably from 20 to 60° C. Any amount of TosMICcan be used. Preferably, the TosMIC is present in a range of 0.8 to 2.0moles, more preferably 1.0 to 1.5 moles per one mole of the aldehyde orcompound of Formula [I] used. The reaction is favorably carried out in anitrogen stream or nitrogen atmosphere. The reaction time will differdepending on compounds to be reacted and other conditions, and isusually from several minutes to 48 hours. After the reaction iscompleted, the reaction solution is cooled down, if necessary, andstandard post-treatments yield the target compound.

Process 3: Reaction of an Aldehyde or a Compound of Formula [I] withTosMIC in the Presence of an Organic Base.

Preferred organic bases for use have a pKa of 12 or more. Actualexamples of organic bases include 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU), 1,5-diazabicyclo[4.3.0]non-5-ene,6-dibutylamino-1,8-diazabicylo[5.4.0]undec-7-ene, triethylenediamine,4-(N,N-dimethylamino)pyridine (AP) andN,N,N′,N′-tetramethylethylenediamine. Among them, DBU and AP arefavorably exemplified. These can be used alone or as a mixture of two ormore. The total amount of an organic base used is in a range of 0.9 to10 moles, preferably 1.0 to 3.0 moles per one mole of the aldehyde orcompound of Formula [I] used.

Examples of solvents suitable for use in the reaction of the presentinvention include halogen-type solvents such as methylene chloride,chloroform and dichloroethane; aromatic hydrocarbon-type solvents suchas benzene, toluene, xylene, benzonitrile, benzotrifluoride andchlorobenzene; ester-type solvents such as methyl acetate, ethyl acetateand isopropyl acetate; ketone-type solvents such as acetone, methylethyl ketone, diethyl ketone and methyl isobutyl ketone; ether-typesolvents such as diethyl ether and tetrahydrofuran; and polar solventssuch as acetonitrile. Particularly preferred are solvents that can beused for synthesizing TosMIC or extracting it after post-treatments.Their examples include halogen-type solvents such as methylene chloride;aromatic hydrocarbon-type solvents such as toluene, xylene andchlorobenzene; ester-type solvents such as ethyl acetate; ketone-typesolvents such as methyl isobutyl ketone; THF and acetonitrile. Suchsolvents can be used alone or in any combination of two or more. Anamount of solvent used is in a range of 1 to 1,000 times by weight,preferably 5 to 100 times by weight, based on the weight of an aldehydeor a compound of Formula [I] used.

In an exemplary reaction, an aldehyde or a compound of Formula [I], aTosMIC solution and an organic base are dissolved and mixed in anappropriate solvent, and reacted at a temperature from −20° C. to theboiling point of the solvent used, preferably from 10 to 60° C. Anyamount of TosMIC can be used. Preferably, the TosMIC is present in arange of 0.8 to 1.5 moles, more preferably 0.9 to 1.2 moles per one moleof the aldehyde or compound of Formula [I] used. The reaction isfavorably carried out in a nitrogen stream or nitrogen atmosphere. Areaction time differs depending on compounds to be reacted and otherconditions, and is usually from several minutes to 48 hours. After thereaction is completed, the reaction solution is cooled down, ifnecessary, and standard post-treatments yield the target compound.

These processes of the present invention can be applied when isolatedcrystalline TosMIC is used. They are favorably applied when TosMICproduced by reaction of TosMFA with phosphorus oxychloride, phosgene ordiphosgene, and a tertiary amine, preferably with phosgene and atertiary amine in an aprotic solvent, is used without isolating andpurifying it.

Exemplification

The present invention is described in more detail in reference toExamples, but not limited to the examples.

EXAMPLE 1

To 16 mL of methanol containing 3.1 g of potassium hydroxide were added5.0 g of 2-methoxy-4-nitrobenzaldehyde and a methylene chloride solutioncontaining 5.7 g of TosMIC at room temperature. The mixture was allowedto react at room temperature until high-performance liquidchromatography (HPLC) found no trace of the starting materials. Upon thecompletion of the reaction, the reaction solution was washed with water,and the solvents were distilled off. The target compound wascrystallized from methanol and water, filtrated and dried to give 5.6 gof the compound (yield: 92%).

EXAMPLE 2

To 3.6 g of 2-methoxy-4-nitrobenzaldehyde and a toluene solutioncontaining 4.1 g of TosMIC was added 20 mL of a methanol solutioncontaining 2.3 g of potassium hydroxide at room temperature. The mixturewas allowed to react at room temperature until HPLC found no trace ofthe starting materials. Upon the completion of the reaction, thereaction solution was washed with water. An HPLC analysis showed thatthe organic layer contained 4.2 g of the target compound (yield: 96%).

EXAMPLE 3

To 36 g of 2-methoxy-4-nitrobenzaldehyde and a chlorobenzene solutioncontaining 43 g of TosMIC was added 200 mL of a methanol solutioncontaining 23 g of potassium hydroxide at room temperature. The mixturewas allowed to react at room temperature until HPLC found no trace ofthe starting materials. Upon the completion of the reaction, thereaction solution was washed with water. An HPLC analysis showed thatthe organic layer contained 39 g of the target compound (yield: 88%).

EXAMPLE 4

To 2 mL of ethylene glycol containing 0.24 g of potassium hydroxide wasadded 0.36 g of 2-methoxy-4-nitrobenzaldehyde at room temperature Tothis solution, 8.98 g of a methylene chloride solution containing 0.46 gof TosMIC was added dropwise. The mixture was allowed to react withstirring at room temperature until HPLC found no trace of the startingmaterials. Upon the completion of the reaction, the reaction solutionwas concentrated. An HPLC analysis showed that the concentrate contained0.38 g of the target compound (yield: 86%).

EXAMPLE 5

To 2 mL of ethylene glycol containing 0.17 g of sodium hydroxide wasadded 0.37 g of 2-methoxy-4-nitrobenzaldehyde at room temperature. Tothis solution, 9.3 g of a methylene chloride solution containing 0.45 gof TosMIC was added dropwise. The mixture was allowed to react withstirring at room temperature until HPLC found no trace of the startingmaterials. Upon the completion of the reaction, the reaction solutionwas concentrated. An HPLC analysis showed that the concentrate contained0.36 g of the target compound (yield: 82%).

EXAMPLE 6

140.2 g (0.65 mol) of N-(4-methylbenzenesulfonylmethyl)-formamide and1.3 L of methylene chloride were placed in a reaction vessel, and keptbelow 5° C. by cooling in an ice bath. Then, 82.2 g (0.85 mol, molarratio: 1.3) of phosgene was bubbled into the solution over 30 minutes,followed by adding 138.6 g (1.4 mol, molar ratio: 2.1) of triethylaminediluted with 195 mL of methylene chloride into the solution dropwiseover 30 minutes at the same temperature. To the obtained orange-coloredreaction solution was added 28 g (molar ratio: 0.3) of a 28% aqueoussolution of sodium hydroxide diluted with 1.5 L of water. The resultingsolution was stirred at about 5° C. for 30 minutes. The solution wasseparated by a separating funnel to give 2096.0 g of the organic layer.A quantitative HPLC analysis showed that the organic layer contained111.3 g of TosMIC (yield: 88%). (Step 1)

98.4 g of 2-methoxy-4-nitrobenzaldehyde was dissolved in 552 mL ofethylene glycol containing 71.2 g of potassium hydroxide and 110 mL ofmethylene chloride, heated to 42 C, and added to the methylene chloridesolution containing 111.3 g of TosMIC that was obtained in Step 1. Themixture was allowed to react at 42° C. until HPLC found no trace of thestarting materials. Upon the completion of the reaction, the reactionsolution was separated. The methylene-chloride layer was washed withwater. The solvents were distilled off. The target compound wascrystallized from methanol and water, filtrated and dried to give 102.4g of the compound (yield: 86%). (Step 2)

EXAMPLE 7

530 mL of methanol containing 75.1 g of potassium hydroxide was added atroom temperature to a chlorobenzene solution containing 110 g of TosMICwith 97 g of 2-methoxy-4-nitrobenzaldehyde added. The mixture was keptreacting at 42° C. until HPLC found no trace of the starting materials.Upon the completion of the reaction, the reaction solution wasseparated. The chlorobenzene layer was washed with water. The solventwas distilled off. The target compound was crystallized fromchlorobenzene, filtrated and dried to give 103.4 g of the compound(yield: 87.7%).

EXAMPLE 8

To 19.7 g of a methylene chloride solution containing 0.99 g of TosMICwas added 1.10 g of p-nitrobenzylidene aniline. To the resultingsolution, 5 mL of methanol containing 0.70 g of potassium hydroxide wasadded dropwise. The mixture was allowed to react with stirring at roomtemperature until HPLC found no trace of the starting materials. Uponthe completion of the reaction, the reaction solution was washed withwater and concentrated. The target compound was recrystallized frommethanol, filtrated and dried to give 0.78 g of the compound. Ananalysis showed that the filtrate contained 0.31 g of the compound(yield: 83%).

EXAMPLE 9

0.24 g of potassium hydroxide was added to 2 mL of ethylene glycol and 2mL of methylene chloride, and heated to dissolve. To this solution, 8.66g of a methylene chloride solution containing 0.46 g of TosMIC with 0.36g of 2-methoxy-4-nitrobenzaldehyde dissolved was added dropwise. Themixture was heated to 42° C. and allowed to react until HPLC found notrace of the starting materials. Upon the completion of the reaction,the ethylene-glycol layer and methylene-chloride layer were separated.The latter was concentrated to give 0.41 g of the target compound(yield: 93%).

EXAMPLE 10 Preparation of 5-(2-methoxy-4-nitrophenyl)oxazole

To an aqueous solution containing 0.16 g of sodium hydroxide were added0.36 g of 2-methoxy-4-nitrobenzaldehyde, 8.1 g of a methylene chloridesolution containing 0.43 g of TosMIC which was obtained in the same wayas Step 1 of Example 6 and 0.08 g of DBU at room temperature. Themixture was heated to 40° C. and kept reacting until HPLC found no traceof the starting materials. Upon the completion of the reaction, thereaction solution was cooled down to room temperature, washed with waterand dried over anhydrous magnesium sulfate. The solvents were distilledoff. An HPLC analysis showed that the concentrated residue contained0.37 g of the target compound (yield: 85%).

EXAMPLE 11 Preparation of 5-(4-nitrophenyl)oxazole

To an aqueous solution containing 0.84 g of sodium hydroxide were added0.45 g of 4-nitrobenzaldehyde, 12.2 g of a methylene chloride solutioncontaining 0.65 g of TosMIC which was obtained in the same way as thatof Example 6 and 0.10 g of tetrabutyl ammonium bromide at roomtemperature. The mixture was allowed to react at room temperature untilHPLC found no trace of the starting materials. Upon the completion ofthe reaction, the reaction solution was washed with water and dried overanhydrous magnesium sulfate. The solvents were distilled off. An HPLCanalysis showed that the concentrated residue contained 0.82 g of thetarget compound (yield: 93%).

EXAMPLE 12

To 0.36 g of 2-methoxy-4-nitrobenzaldehyde and 8.5 g of a methylenechloride solution containing 0.45 g of TosMIC which was obtained in thesame way as that of Example 6 was added 0.60 g of DBU at roomtemperature. The mixture was allowed to react at room temperature untilHPLC found no trace of the starting materials. Upon the completion ofthe reaction, the reaction solution was washed with water and dried overanhydrous magnesium sulfate. The solvent was distilled off. An HPLCanalysis showed that the concentrated residue contained 0.47 g of thetarget compound (yield: 96%).

APPLICABILITY IN INDUSTRY

As described above, according to the process of the present invention,5-substituted oxazoles and 5-substituted imidazoles, which are useful asagricultural chemicals, drugs, functional materials, and others and asintermediates to produce them, can be prepared safely and efficiently.

1. A process for the preparation of a 5-substituted oxazole or5-substituted imidazole comprising synthesizingp-tolylsulfonylmethylisocyanide from N-(p-tolylsulfonylmethyl)formamidewith phosphorus oxychloride, phosgene or diphosgene, and a tertiaryamine, to form a p-tolylsulfonylmethylisocyanide solution which is notisolated and purified as crystals, washing thep-tolylsulfonylmethylisocyanide solution with an aqueous alkalinesolution, and reacting the p-tolylsulfonylmethylisocyanide solution withan aldehyde or a compound represented by Formula (I):R¹CH═NR² wherein, R¹ and R² are optionally substituted phenyl,optionally substituted heterocyclic group or optionally substitutedalkyl, wherein the p-tolylsulfonylmethylisocyanide solution is reactedwith an aldehyde or a compound of Formula (I) in a mixed solvent of anaprotic solvent and a protic solvent in the presence of potassiumhydroxide or sodium hydroxide or mixtures thereof.
 2. A processaccording to claim 1 in which the protic solvent is one or more solventsselected from the group consisting of water, C₁ to C₁₀ alcohols andmono- or alcohols, mono-alkylene glycols and poly-alkylene glycols.
 3. Aprocess for the preparation of a 5-substituted oxazole or 5-substitutedimidazole comprising synthesizing p-tolylsulfonylmethylisocyanide fromN-(p-tolylsulfonylmethyl) formamide with phosphorus oxychloride,phosgene or diphosgene, and a tertiary amine, to form ap-tolylsulfonylmethylisocyanide solution which is not isolated andpurified as crystals, washing the p-tolylsulfonylmethylisocyanidesolution with an aqueous alkaline solution, and reacting thep-tolylsulfonylmethylisocyanide solution with an aldehyde or a compoundrepresented by Formula (I):R¹CH═NR² wherein, R¹ and R² are optionally substituted phenyl,optionally substituted heterocyclic group or optionally substitutedalkyl, wherein the aldehyde or the compound of Formula [I] is reactedwith p-tolylsulfonylmethylisocyanide in a mixed solvent of an aproticsolvent and water in the presence of an inorganic base and between about0.0001 moles and about 5 moles of at least one phase-transfer catalystselected from the group consisting of quaternary ammonium salts andsalts, quaternary phosphonium salts and an inorganic base, salts, crowncompounds and organic bases.
 4. A process for the preparation of a5-substituted oxazole or 5-substituted imidazole comprising synthesizingp-tolylsulfonylmethylisocyanide from N-(p-tolylsulfonylmethyl) formamidewith phosphorus oxychloride, phosgene or diphosgene, and a tertiaryamine, to form a p-tolylsulfonylmethylisocyanide solution which is notisolated and purified as crystals, washing thep-tolylsulfonylmethylisocyanide solution with an aqueous alkalinesolution, and reacting the p-tolylsulfonylmethylisocyanide solution withan aldehyde or a compound represented by Formula (I):R¹CH═NR² wherein, R¹ and R² are optionally substituted phenyl,optionally substituted heterocyclic group or optionally substitutedalkyl, wherein the aldehyde or the compound of Formula [I] is reactedwith p-tolylsulfonylmethylisocyanide in halogen-type solvents, aromatichydrocarbon-type solvents, ester-type solvents, ketone-type solvents,ether-type solvents, or polar solvents in the presence of an organicbase which has a pKa of 12 or more.
 5. A process according to claim 4 inwhich the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene or4-(N,N-dimethylamino)pyridine.
 6. The process according to claim 1wherein the aldehyde is an unsubstituted or substituted aromaticaldehyde.
 7. The process according to claim 3 wherein the aldehyde is anunsubstituted or substituted aromatic aldehyde.
 8. The process accordingto claim 4 wherein the aldehyde is an unsubstituted or substitutedaromatic aldehyde.